SUMMARY Mammalian aging is accompanied by functional defects in a wide range of tissues that contain pools of stem cells. Age-dependent stem cell deficiencies may underlie defects in tissue physiology during aging. Exciting recent studies have revealed that a number of age-dependent defects in stem cells could be `rejuvenated' by specific interventions, including for example heterochronic parabiosis. The program has identified epigenetic changes that occur during stem cell aging. Thus a central question is whether rejuvenating interventions also rejuvenate the epigenetic and transcriptional state of old cells, and could this knowledge help `epigenetically reprogram' cells from an older state to a younger state. This Rejuvenating Strategies Core proposes to explore epigenetic changes in different types of adult stem cells simultaneously isolated from young and old mice in response to four rejuvenating strategies administered to old mice and young controls: heterochronic parabiosis, exercise, the mTOR inhibitor rapamycin and fasting/dietary restriction. The stem cells that will be simultaneously isolated following these interventions include stem cells from muscle, brain, and blood. Specifically, the Core will perform the following: 1 House wild-type mice from the NIA's Aging Mouse Colony for simultaneous analysis of aging and rejuvenation of epigenetic changes in stem cells by the three laboratories of the Program Project; 2. Implement four rejuvenation strategies ? heterochronic parabiosis, exercise, rapamycin, and fasting/dietary restriction cycle ? to young and old mice; 3. Ensure that the logistics of the rejuvenating interventions and simultaneous stem cell isolation from the same cohort of mice is in place for all three labs in order to allow meaningful cross-comparisons between different tissue stem cells that are the focus of the Program Project. This Core will couple the exciting concept of rejuvenation strategies to cutting-edge stem cell isolation and epigenomic studies. Having common aged cohorts, controlled experimental designs for rejuvenation interventions, and simultaneous collection of different stem cells from the same animals will enhance success and allow cross comparison. Characterizing the epigenetic changes that occur during stem cell aging and rejuvenation will be a key step in implementing `epigenetic reprogramming', with the goal of enhancing tissue function during aging and delaying the onset of age-related diseases.